This research project encompasses a number of different approaches to both understand how current antitubercular chemotherapy works using the most modern technologies and to use this information to develop new and improved therapies and therapeutic approaches. Individual projects within this framework are aimed at; (1) understanding the biochemical mode of action of existing front-line antituberculars such as isoniazid, pyrazinamide and ethambutol, (2) understanding the action of various agents in animal models of tuberculosis therapy, and (3) understanding the development of resistance within patients undergoing chemotherapy. The project relies on the development of advanced animal models for predicting drug efficacy under real world conditions. In addition, development of screening assays that would predict drugs able to shorten the current duration of therapy or treat latent infections have been a large focus. Section scientists have also been involved in understanding the mechanism of action of second-line antituberculars and the evolution of multidrug resistance in patients in South Korea and Cambodia. A Natural History clinical research protocol is in the final stages of IRB approval, an IRB has been constituted in South Korea, and GCP training of staff at the clinical research site in South Korea has been completed. In addition, a Phase I clinical trial of pimonidazole, a marker of hypoxic tissues, has been initiated in South Korea and is in the final stages of IRB approval and registration with the Korean FDA.